HIV dementia (HIVD) can play a significant role in the clinical course of an HIV infection. HIVD is thought to affect 20-30% of patients with HIV infections. Because macrophages in the perivascular space and microglial in the parenchyma are thought to be the primary sites of HIV infection in the central nervous system (NS), these cell types are likely to play a critical role with pathogenic events that lead to HIVD. In this study we propose to develop a small animal model in which we can study HIV infection of these cell types in the CNS and pathogenic mechanisms that are a consequence of this infection. Towards that end we have developed a novel SCID-hu model, SCID-hu BTL (Bone-Thy/liv-Lymph node), that allows seeding of the murine CNS with human macrophages in the perivascular spaces (choroid plexus and meninges) and human microglia in the parenchyma. We will take advantage of our expertise with the development of SCID-hu models, the biology of human hematopoietic stem cells (HSC) and gene modification of HSC to carry out the following specific goals: (1) Determine the tissue and progenitor source of human macrophages and microglia that seed the CNS in SCID-hu BTL (Bone-Thy/liv-Lymph node) mice, (2) Examine tropism requirements for HIV infection and pathogenesis in the CNS of SCID-hu BTL mice and (3) Examine non-infectious mechanisms of neuropathogenesis and their genetic basis in the SCID-hu BTL model.